Niacin is an important dietary supplement. For example, niacin plays an important role in metabolism, acting as an hydrogen and electron transfer agent in carbohydrate metabolism. Furthermore, niacin forms part of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are important intercellular carriers of reducing electrons in the electron transport system in living organisms. Moreover, niacin containing coenzymes participate in a variety of biological reactions, e.g., lipid catabolism and oxidative deamination. In fact, niacin deficiency has been identified as the leading cause of a medical malady known as pellagra.
Niacin has also been found to have therapeutic value. It is highly effective in reducing elevated levels of plasma cholesterol and triglycerides, and is thus useful in treating hypercholesterolemia. In addition, niacin exhibits adipose tissue lipolysis, reduces plasma free fatty acid levels and decreases very low density lipoprotein synthesis. In addition, niacin has demonstrated value in preventing manifestations of arteriosclerotic heart disease.
To administer niacin as a diet supplement, the present inventor sought to make tablets containing same since tablets have shown to be one of the best methods for administering pharmaceuticals.
Tablets have several advantages over capsules. For example, for some drugs, it is recommended that the patient begin taking a smaller dose and gradually over time increase the dose to the desired level; this regimen can help avoid undesirable side effects. Tablets are preferable to capsules in this regard because a scored tablet easily can be broken to form a smaller dose.
In addition, tableting processes are generally simpler and less expensive than bead coating and capsule formation. Further, tablets can be safer to use because they may be less subject to tampering.
In common tableting processes, material which is to be tableted is deposited into a cavity and one or more punch members are then advanced into the cavity and brought into intimate contact with the material to be pressed, whereupon a compression force is applied. The material is thus forced into conformity with the shape of the punches and the cavity.
Three basic compression steps are common to most tableting operations, i.e., direct dry compression, wet granulation and dry granulation.
Direct compression was historically used to describe compression of a single crystalline compound into a compact tablet form without the use of additional ingredients. However, direct compression techniques are encumbered by a number of problems; few compounds possess the necessary properties to make such compaction possible. In addition, in direct compression, the flow properties of particle-sized powders are inadequate to ensure even filling of the die cavities of tablet presses. Furthermore, entrapment can occur, which interferes with the formation of the tablet.
Where direct compression is not possible, granulation has been used as a pretreatment. This technique is most frequently used. Materials to be delivered are pretreated to form granules that readily lend themselves to tableting. As commonly defined, “granulation” is any process of size enlargement whereby small particles are gathered together into larger permanent aggregates to yield a free flowing composition having a consistency similar to that of dry sand. This may be accomplished by agitation in mixing equipment or by compaction, extrusion or globulation. In granulation, the active or intended ingredients are generally admixed with a compression vehicle. The compression vehicle or filler must have good compressibility, good flowability and stability under normal ambient conditions as well as being low in cost and satisfactory in both texture and appearance. In addition to compression vehicles, tablet formulations typically include other additives such as diluents, flavor, colors, disintegrating agents and lubricants, all of which may be added during granulation or thereafter.
Although the wet granulation and the dry granulation methods are the most commonly used, each of these techniques requires several steps in order to prepare the drug. For example, the wet granulation process typically includes mixing the components, usually in powder form, preparing the granulating binder solution, thoroughly mixing the components with the granulating binder solution to form a dough, coarse screening the mess through a sleeve, drying, grinding, adding a lubricant and compressing the tablets from the resulting mixture. Dry granulation involves the steps of mixing the powder components, compressing the mixture into hard slugs, grinding the slugs into desired particle size, screening, adding fillers, if necessary, and compressing the mixture into tablets.
These are the general steps normally used to make conventional immediate release dosage forms. However, modifications have been made to prepare sustained release formulations.
Sustained release formulation for drugs are prepared in such a manner as to effect sustained or slow release into the gastro-intestinal digestive tract of humans or animals over an extended period of time. They have several advantages over conventional immediate release dosage forms. For example, there is less frequent administration of the active ingredient and more frequent resultant patient regime compliance, thereby avoiding the problems inherent in ensuring timely consumption thereof by the patient. Moreover, sustained release formulations achieve a small sustained blood level response to active ingredient in the formulation relative to conventional immediate release drug forms. It also reduces or possibly eliminates toxic or side effects which are caused by frequent administration of active ingredients through the peaks and valleys of blood levels caused by multiple ingestion thereof. By providing a slow and steady release of the active ingredient over time, absorbed concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood level response.
Sustained release therapeutic dosage forms are based on many and varied principles. For example, one of the techniques of these preparations involves formation of the drug in generally spherical pellet forms wherein a specific quantity of pellets are set aside for immediate release and the remaining dry pellets or spheres are coated with various thicknesses of a suitable fat or fatty resinous like coating. When fractions of the pellet are blended together and then filled into capsules or pressed into tablets without destroying the integrity of the coating, suitable slow or sustained release forms may be effected. Another technique is to admix the therapeutic agent with fats and solid polyhydric alcohols, such as polyoxyethylene glycol distearate, and press the mixture into tablets to form an erosion matrix to effect slow or sustained release dosage forms. Another method employs the use of a therapeutic agent bound to an ion exchange resin or otherwise complexed with an organic or inorganic molecule and embedded in a waxy core or granule and administered in capsule or pressed tablet form. Still another method employs the use of an indigestible film former such as methyl cellulose applied to a powder or granule base containing a therapeutic agent followed by subsequent forming into compressed tablets to effect slow or sustained release. Yet, another method employs a tablet containing a specific drug coated with an indigestible film in which the film is pierced by a layer beam to allow for a small and precise portal from which the drug is slowly released.
Although these are just a few examples of some of the techniques utilized to prepare sustained release formulations, the point is clear. These techniques require several steps, utilizing sophisticated procedures. The present inventor sought a much simpler procedure which is more efficient and only requires a few steps.
Recently, less complicated procedures have been utilized to prepare sustained release formulations as described hereinbelow.
U.S. Pat. No. 5,292,534 discloses a sustained release composition for various active ingredients, including niacin, in mixture with Xanthum gum and lubricant.
Gaylord, et al. in U.S. Pat. No. 4,795,327 disclose a method for the preparation of a therapeutically active solid unit dosage form having a controlled and prolonged release pattern upon administration consisting of compressing and shaping a mixture of a therapeutically active medicament and a carrier based material consisting of a mixture of one or more water-soluble nonionic cellulose ethers and an anionic surfactant, and wherein at least one of the cellulose ethers is methyl cellulose or hydroxypropylmethylcellulose having a number average molecular weight of at least 50,000. It discloses that the anionic surfactant was necessary, for in its absence, the tablet exhibited a very poor release profile.
U.S. Pat. No. 4,983,398 to Gaylord, et al. discloses another method for the preparation of a therapeutically active unit dosage form having a controlled and sustained release pattern upon administration comprising mixing, shaping and compressing a therapeutically active medicament and a carrier base material consisting essentially of (a) an alkali metal carboxylate and (b) one or more water-soluble nonionic cellulose ethers, at least one of which is hydroxypropylmethylcellulose having a number average molecular weight of at least 50,000. They show that the presence of the alkali metal carboxylate is necessary to retard the release rate of the drugs.
U.S. Pat. No. 4,775,535 to Lowey, disclose a method of preparing controlled release pharmaceutical tablets, by adding a cellulose ether base material, e.g., hydroxypropylmethylcellulose, and an active therapeutic agent to form a mixture, thoroughly and uniformly mixing that mixture, discontinuing the mixing and permitting the uniform mixture to stand for a period of time, typically two to 24 hours or longer, sufficient to cause the therapeutic agent to become bonded to the carrier base material and compressing the mixture to form the solid unit dose tablets.
U.S. Pat. No. 4,734,285 describes a process for providing sustained release solid tablets of a therapeutically active composition comprising:
(a) comminuting a water-soluble hydroxy-propyl methylcellulose ether having a hydroxy propoxy substitution of from about 7 to about 12 weight percent, a methoxy substitution of from about 28 to about 30 weight percent, and a number average molecular weight of at least 50,000 to a relatively fine particle sized cellulose ether composition, having 2% aqueous solution viscosity of at least 800 cps and at least 90% by weight of the cellulose ether particles pass through a 100 mesh screen, and
(b) intimately mixing the active composition in the form of a powder with a functionally effective amount of fine particle sized cellulose ether composition and
(c) subjecting the mixture of active composition and fine particle sized cellulose ether composition to compression conditions to form a solid tablet.
U.S. Pat. No. 5,268,181 discloses the preparation of niacin tablets containing hydroxypropylmethylcellulose, hydrogenated vegetable oil, and silicon dioxide utilizing the wet granulation processes. For example, 16 liters of water were heated in 95° C. in a stainless steel container and hydroxypropylmethylcellulose was mixed therewith until a homogenous suspension was obtained. 48 liters of water was added until a clear solution was obtained. Then hydrogenated vegetable oil, which was sized through a No 1 mesh screen and coloring was added thereto. Niacin powder was added thereto and 22 additional Methocel®E15LV (hydroxypropylmethylcellulose) was sprayed on and mixed and the resulting wet granulation was sized through a USS No 16 screen, and dried. It also discloses the formulation of the niacin tablets using a fluid bed process, which process is similar to the one described herein above except it was prepared in a fluid bed container.
U.S. Pat. No. 5,023,245 discloses the preparation of niacin formulations in which the niacin is in combination with a gel-forming dietary fiber, such as guar gum. It discloses the preparation of a niacin tablet by granulating the niacin in a fluid bed granulator by spraying the niacin powder with NaCMS and ethyl cellulose to form granulated niacin (95%). 160 mg of the niacin was then mixed with psyllium husk powder (600 mg) or other gel forming dietary fiber, calcium carbonate (100 mg), citric acid (25 mg) and microcrystalline cellulose (25 mg).
However, even many of these processes described hereinabove were quite complex. Many of these formulations required components, which, in a simpler process, could be eliminated. The inventor sought to prepare a formulation which was simpler and did not require as many components. In addition, in many of the processes described hereinabove, the processes required several steps, which affected the cost and efficiency of the process. The inventor sought a process which is much simpler than those and which provided an excellent release profile.
However, there are many factors which must be considered in making a sustained release formulation, some of which are general and some of which are specific to the active ingredient. For example, the sustained release formulation must have an excellent drug release profile, and yet, it must be stable and have a long shelf life. Furthermore, it is of considerable importance in the administration of controlled long acting release tablets that the rate of release of the active agent from the tablet be consistent and uniform among tablets prepared at different times and in different manufacturing batches. It is critical both from the standpoint of safety as well as the reliability thereof that the bioavailability characteristics of the tablet prepared be substantially uniform and comparable. In the absence of such reliability, the dangers to a patient are significant, especially if active ingredients are released at faster or slower rate than are assumed. Moreover, niacin itself presents a problem. The classic concept of a sustained release dosage regime is to release 20–35% of the therapeutic agent within the first hour and to sustain the remaining portion of the therapeutic agent over a 8–12 hour period. This is problematic especially since the niacin therapeutic dose is 500–1000 mg and especially since niacin causes a flushing response in most subjects with a dosage release of more than 75 mg within a one hour period. In addition, niacin in concentrations greater than 50% by weight has been found difficult to compress into a tablet using direct compression methods. Further, niacin in powder form shows very poor compressibility and flow properties. But to make tablets of niacin, it is essential that the medicament is compressible and exhibits good flow properties.
However, the present inventor has found a means of overcoming these difficulties and has found a process for producing a sustained release oral dosage form of niacin that is prepared in relatively few steps and which is stable, has a long shelf life and exhibits an excellent drug release profile. Moreover, the drug release profile of the sustained release formulation is uniform and consistent among tablets prepared in a given manufacturing batch and among tablets prepared at different times and in different manufacturing batches.